Microbubbles accelerate thrombolysis in peripheral arterial occlusions: how does the technology work?
Kakkhee Yeung, M.D., Ph.D. Hillian Nederhoed, Harm Ebben, Rene Musters, Willem Wisselink
Department of Vascular Surgery and Physiology Institute of Cardiovascular Resarch VU
VU University Medical Center Amsterdam, The Netherlands
ICaR-VU
Disclosure
Speaker name:
Kakkhee Yeung
I have the following potential conflicts of interest to report:
Consulting
Employment in industry
Stockholder of a healthcare company
Owner of a healthcare company
Other(s)
I do not have any potential conflict of interest X
Introduction
• Acute peripheral arterial occlusions • Therapy: catheter directed thrombolytic infusion with urokinase,
(r)tPA:
- NL: urokinase - Time consuming - Cave: major haemorrhagic complications 6-13%, 2% intracranial haemorrhages*
* STILE, TOPAS
Better, Safer and Faster Thrombolysis is needed
• Heavy gas filled particles with lipid shell • Tiny microbubbles oscillate when subjected to low intensity ultrasound (US) and can
cavitate when subjected to high intensity US
Microbubbles
Courtesy to N de Jong
Advantages of microbubbles
Non-specific mechanical effects ! thrombus breakdown due to mechanical force of microbubbles + ultrasound
Catheter +UK
Clot
Advantages of microbubbles
Carry thrombolytics to the specific thrombus
NO CATHETER NEEDED
clot
= FLUORESCENT LABELED UROKINASE
ON THE OUTER LIPID SHELL INCORPORATED IN THE BUBBLE
In vitro study ! !
MORE PRECISE DELIVERY AND NO NEED FOR A CATHETER
How does the technology work?
source: video by H.P. Ebben, courtesy footage Alexandrov, Stroke university
Aim
Non-specific mechanical effects: thrombus breakdown due to mechanical force
of microbubbles + ultrasound
Improve thrombolysis for acute peripheral occlusions by using microbubbles and concomitant application of ultrasound Reduce therapy time and thrombolytic dose
Methods
• Animal model: pilot study • Yorkshire pigs 60-80kg • Thrombus: 100U Bovine Thrombine
High intensity ultrasound
Local low intensity ultrasound
High intensity ultrasound
EKOS catheter catheter
Targeted Microbubbles carrying UK: 5x5 mL in 1hour
Microbubbles 5x5mL in 1 hour
Microbubbles 5x5mL in 1 hour
catheter
Urokinase: 500.000 IU UK bolus
50.000 IU UK/ hour for 3 hours
Urokinase: 500.000 IU UK bolus
50.000 IU UK/ in 1 hour
Control group
N=4 N=6 N=4 N=5
End points
• Flow distal to the occlusion in the external iliac artery • Thrombus weight at the end of the experiment • Haemorrhagic complications
Results
Flow in the external iliac artery 3 hours after therapy
Groups
Reperfusion at the end of the experiment
Control group: standard therapy: catheter + UK 1/4
microbubbels + ultrasound+ catheter + UK 4/6
microbubbels + ultrasound+ EKOScatheter + UK 4/4
targeted microbubbels carrying UK + ultrasound 3/5
Results Thrombus weight (gr) at the end of the experiment
No haemorrhagic complications were observed during autopsy.
Control group
Microbubbels catheter + UK
Microbubbels EKOS + UK
Targeted microbubbels + UK
Conclusion
• Application of ultrasound with infusion of microbubbles could improve thrombolytic therapy
• Targeted microbubbles carrying urokinase is a potential option for thrombolysis without the need for a catheter
Amsterdam, the Netherlands
Project group K.K. Yeung J.H. Nederhoed H.P. Ebben A.W.J. Hoksbergen W. Wisselink J.D. Blankensteijn R.F.J. Kwekkeboom R.J.P. Musters G.J. Tangelder J. Slikkeveer O. Kamp R.J. Lely
Departments of Vascular Surgery Physiology Cardiology Radiology
Microbubbles accelerate thrombolysis in peripheral arterial occlusions: how does the technology work?
Kakkhee Yeung, M.D., Ph.D. Hillian Nederhoed, Harm Ebben, Rene Musters, Willem Wisselink
Department of Vascular Surgery and Physiology Institute of Cardiovascular Resarch VU
VU University Medical Center Amsterdam, The Netherlands
ICaR-VU
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